Asthma is a common chronic inflammatory disorder of the airways. The number of sufferers has increased dramatically over recent decades and the World Health Organisation estimates that in the region of 300 million people worldwide suffer from asthma. Allergic asthma is characterised by uncontrollable airways hyperresponsiveness (AHR) induced by a variety of provocative stimuli and is associated with type-2 inflammatory infiltrates into the lungs.
Type-2 cytokines play an important role in mediating protective immunity to parasitic helminth infection, regulating effector functions such as B cell growth and IgE secretion, inducing goblet cell hyperplasia and associated mucus production, eosinophilia, mastocytosis and fibrosis (1). It is the central roles played by these cytokines in the regulation of these effector functions that have made them key therapeutic targets in asthma. Indeed, mouse models in which these cytokines are over-expressed show significant characteristics of asthma. Surprisingly then, efforts to ameliorate experimental asthma by blocking specific type-2 cytokines have, with the exception of inhibiting IL-13, proven unsuccessful.
Inhibition of IL-13 suppresses both AHR and airway inflammation although the mechanism remains unclear (2, 3). However, given the complex pathophysiology and poorly understood etiology of asthma, it is uncertain whether targeting individual pathways will ultimately prove successful therapeutically.
Recently, over-expression of IL-25/IL-17E, a member of the structurally related IL-17 cytokine family (8), has been shown to induce type-2 responses in vivo (4-6) and increase responsiveness to airway agonists (7). Il25−/− mice failed to expel helminth parasites; a key indicator of an ineffectual type-2 response (9, 10).
The basic structure of an antibody is well known in the art. A naturally-occurring antibody usually has four polypeptide chains: two identical heavy chains and two identical light chains connected by disulphide bonds. The heavy and light chains each have a constant region and a variable region (or domain). The variable regions are primarily responsible for antigen binding. Within each variable region, three subregions, known as the complementarity-determining regions (CDRs), make contact with the antigen. The CDRs of each variable domain are numbered, from the N-terminal to the C-terminal, as CDR1, CDR2 and CDR3. Between and N- and C-terminal to the CRDs are four so-called framework regions, which make few if any contacts with the antigen. More details regarding the structures of antibodies are illustrated in many of the documents cited below, which are incorporated herein by reference.